tbuckley/cabot-search huggingface dataset:
Abstract 2334: Inhibition of DHFR modulates anti-tumor immunity
Authors: Austin Boese, Isabelle Young, Jihoon Kang, Courteney Malin, Jung Seok Hwang, Sumin Kang
Journal: Cancer Research (2022)

Abstract Lung cancer is the second most common type of cancer in both men and women and has the highest mortality rate. Non-small cell lung cancer (NSCLC) makes up most cases. Immune checkpoint inhibitors have significantly improved the clinical management of some NSCLC cases, yet many lung cancer patients still fail to respond to conventional immunotherapy. Therefore, more research is needed to characterize cellular pathways contribute to immune checkpoint inhibitor (ICI) resistance in NSCLC patients. Dysregulated cellular metabolism is a common feature of many cancer types, and metabolites are now known to modulate several functions inside cells such as signaling pathways and epigenetic control of gene expression. Therefore, targeting tumor metabolism may be able to combat NSCLC immunotherapy resistance. To identify potential metabolic pathways involved in the anti-tumor immune response, we employed a metabolic inhibitor-based drug screen in human NSCLC cell lines and tested for expression changes in a panel of known immune regulator genes. Notably, pharmacologic inhibition of dihydrofolate reductase (DHFR) downregulated the mRNA expression of anti-phagocytic surface protein cluster of differentiation 24 (CD24) in lung cancer cells. In line with this, shRNA knockdown and overexpression of DHFR, decreased and increased CD24 RNA and protein levels, respectively. These results show that the metabolic enzyme DHFR is involved in CD24 gene expression. Cancer cells heavily rely on DHFR for enhanced nucleotide biosynthesis to facilitate rapid tumor growth, and DHFR inhibitors are already used in the clinic for cancer therapy. This study highlights a novel interaction between reprogrammed cancer metabolism and the anti-tumor immune response, with possible clinical implications for DHFR inhibitors such as methotrexate in combination with conventional cancer immunotherapy agents. Citation Format: Austin Boese, Isabelle Young, Jihoon Kang, Courteney Malin, Jung Seok Hwang, Sumin Kang. Inhibition of DHFR modulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2334.
Abstract 1583: The interaction of stromal components and tumor cells dictates the tumor progression and clinical outcomes in stomach cancer
Authors: Seungho Lee, Taemin Kim, Jaeho Cheong, Hyongbum Kim, Sunghwan Lee
Journal: Cancer Research (2022)

Abstract A subset of gastric cancers (GC) show activated epithelial-to-mesenchymal transformation (EMT), but it is of debate as to the origins of the EMT signals (i.e., from tumor cells or microenvironments) and how they are associated with clinical outcomes. In this study, we observed that mesenchymal GCs comprising 30-40% of datasets showed elevated level of infiltrating stromal cells and worse clinical outcomes. The analysis of xenograft sequencing revealed that the transcriptional signals representing EMT mainly come from stromal cells instead of tumor cells. In addition, no evidence of tumor-originating, EMT-driven stromal cells was found in single cell RNA sequencing data. Interestingly, expression of EMT signature genes in primary tumor was highly correlated with that of mouse genes. Microenvironment profiling identified a specific T cell subtypes associated with mesenchymal GCs such as T cell gamma-delta. Finally, deconvolution-based tumor, immune and stromal cells in mesenchymal GCs showed the YAP1 activation, representing the consequences of interactions of stromal component and cancer as well as defining the intrinsic and extrinsic hallmarks of mesenchymal GCs. Citation Format: Seungho Lee, Taemin Kim, Jaeho Cheong, Hyongbum Kim, Sunghwan Lee. The interaction of stromal components and tumor cells dictates the tumor progression and clinical outcomes in stomach cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1583.
Abstract 5723: JDP2 interacts with p53 and enhances p53 transactivation and stability
Authors: Wei-Hsiung Yang, Kasey Price, Leticia Cardoso, William Yang, Chiung-Min Wang, Richard Yang
Journal: Cancer Research (2022)

Abstract USAAP-1 protein mainly consists of proteins belonging to c-Jun, c-Fos, activating transcription factor (ATF), and Jun dimerization protein (JDP) family. In addition to AP-1 site, JDP2 also binds to cAMP responsive element (CRE) site in numerous cis-elements of the target genes. JDP2 has been shown to be involved in cancer development and cell-cycle regulation, suppression of adipocyte differentiation, and controlling bone homeostasis and antibacterial immunity. ATF3 and JDP2 share high similarity in C-terminal domains with identities of 65%. Previous studies have demonstrated that ATF3 can bind to p53 and regulate p53 transcriptional activity and stability. Though couple of studies have shown that JDP2 inhibits expression of p53 and p53 represses the transcriptional activity of JDP2 promoter; however, whether JDP2 directly interacts and regulates p53 transactivation remains largely unknown. Herein, we demonstrate for the first time that JDP2 can directly interact with p53. First, we found that both ATF3 and JDP2 can bind to p53 and the C-terminus of JDP2 is required for p53 binding. Secondly, in p53-null H1299 cells, JDP2 dose-dependently enhances p53 transactivation using p53RE-Luc (14X). Moreover, we demonstrated that JDP2 dose-dependently decreases p53 protein level in consistence with the previous reports. Finally, JDP2 increases p53 stability in CHX chase experiments. Taken together, our results demonstrate that JDP2 directly binds to p53 and enhances p53 transactivation and stability, suggesting that JDP2 is a novel regulator of p53. Citation Format: Wei-Hsiung Yang, Kasey Price, Leticia Cardoso, William Yang, Chiung-Min Wang, Richard Yang. JDP2 interacts with p53 and enhances p53 transactivation and stability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5723.
Abstract 2249: A metabolomic analysis of adiposity measures and pre- and postmenopausal breast cancer risk in the Nurses’ Health Studies
Authors: Kristen D. Brantley, Oana A. Zeleznik, Barbra A. Dickerman, Raji Balasubramanian, Clary B. Clish, Julian Avila-Pacheco, Bernard Rosner, Rulla M. Tamimi, A. Heather Eliassen
Journal: Cancer Research (2022)

Abstract Adiposity is consistently positively associated with postmenopausal breast cancer and inversely associated with premenopausal breast cancer risk. In this nested case-control study of 1651 breast cancer cases and 1651 matched controls from the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHSII), we selected lipids and polar metabolites correlated with BMI, waist circumference, weight change since age 18, or derived fat mass, developed a metabolomic score for each measure using LASSO regression, and used logistic regression to investigate the association between this score and breast cancer risk adjusted for risk factors. Analyses were stratified by menopausal status at blood draw and diagnosis. We further explored risk of ER+ and ER- breast cancer.Metabolite correlations were similar across adiposity measures. Metabolite scores developed among only premenopausal or postmenopausal women were highly correlated with scores developed in all women (r=0.94-0.96). Higher metabolomic adiposity scores were generally inversely related to breast cancer risk among premenopausal women. Among postmenopausal women, significant positive trends with risk were observed for higher metabolomic adiposity scores (e.g., metabolomic waist circumference score OR Q4 v. Q1=1.55, 95% CI=1.08-2.22, p-trend=0.01). Metabolites associated with adiposity and breast cancer risk, glycerophosphocholines and branched-chain amino acids, are also associated with metabolic dysregulation. The same metabolites represented adiposity in pre- and postmenopausal women, though breast cancer risk associations still differed by menopausal status. Thus, metabolic dysregulation may have a differential association with pre- vs. postmenopausal breast cancer. Investigation of these metabolites and their role in adiposity-related breast cancer risk should be further explored. Citation Format: Kristen D. Brantley, Oana A. Zeleznik, Barbra A. Dickerman, Raji Balasubramanian, Clary B. Clish, Julian Avila-Pacheco, Bernard Rosner, Rulla M. Tamimi, A. Heather Eliassen. A metabolomic analysis of adiposity measures and pre- and postmenopausal breast cancer risk in the Nurses’ Health Studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2249.
Abstract 5928: MTA1-targeted interception by natural stilbenes in high-risk prostate cancer
Authors: Anait S. Levenson
Journal: Cancer Research (2022)

Abstract Active surveillance subpopulation of patients with prostate cancer includes men with varying cancer risk categories of precancerous disease due to prostatic intraepithelial neoplasia (PIN) heterogeneity. Identifying molecular alterations associated with PIN can provide preventable measures through finding novel targets for cancer interception, specifically by active dietary polyphenols with potent biological properties including anti-inflammatory, anti-oxidant, and anticancer effects. A large volume of preclinical evidence shows that natural stilbenes produce anticancer responses in a variety of cell lines and animal models of different types of cancer, including solid tumors as well as hematological malignancies. However, identification of a particular target with clinical relevance is rare. I will discuss the potent MTA1-targeted anticancer effects of natural stilbenes (resveratrol, pterostilbene, and Gnetin C) observed in unique preclinical models of prostate cancer mimicking high-risk premalignant tumors with overexpressed MTA1. We have shown that MTA1 cooperates with PTEN deficiency to accelerate high-grade PIN development through MTA1-associated signaling. We further demonstrated that stilbene supplemented diets lead to more favorable histopathology with decreased severity and number of PIN foci accompanied with reduced proliferation, inflammation, and angiogenesis concomitant to reduction of MTA1-associated signaling, including specific miRNAs. Together, our preclinical data provide strong evidence for the potential of stilbenes as promising natural agents for MTA1-targeted interceptive strategy. Human cancer prevention trials for protecting select patients with high MTA1 from developing into full-fledged disease are urgently needed. This can be one extra forward step towards viable and successful interception/chemoprevention potential for prostate cancer with an implication for precision medicine. Supported by NCI/NIH R15CA216070 to ASL. Citation Format: Anait S. Levenson. MTA1-targeted interception by natural stilbenes in high-risk prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5928.
Abstract 3857: A novel microfluidic platform for understanding the role of PDAC stroma in immune response
Authors: Marlene Geyer, Sabrina D'Agosto, Henriëtte Lanz, Vincenzo Corbo, Jos Joore, Karla S. Queiroz
Journal: Cancer Research (2022)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type is estimated to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. PDAC is characterized by high-density stroma and an immunosuppressive tumor microenvironment that lead to a lack of efficacy of immunotherapeutic strategies. Those facts highlight the urgent need for more relevant PDAC in vitro models that support the discovery of novel (immuno-)therapies. Here, we describe the establishment of a multiple cell type culture in a microfluidic platform that will be applied for modeling immune and stroma cell interplay in PDAC. Microfluidic platforms such as the OrganoPlate® support 3D growth and inclusion of different cell types cultured under flow conditions. The aim of this project was to determine the involvement of stromal cells such as endothelial cells and pancreatic stellate cells in immune cell recruitment in pancreatic cancer. In order to generate a more relevant culture set up, supporting cells and PDAC organoids were used in the 3-lane OrganoPlate® to study immune cell recruitment. Migration of fluorescently labelled peripheral blood mononuclear cells from vasculature through the stromal compartment to the PDAC organoids was tracked for 72h using confocal microscopy. Migration of immune cells to the tumor cell compartment was significantly inhibited by the stromal compartment, thus confirming in vivo immune responses, as the stroma seems to form both a physical as well as a chemical barrier for immune cells to reach the active tumor site. Interestingly, PDAC organoid conditioned medium efficiently attracts immune cells into the tumor compartment, indicating that secreted factors play a relevant role in immune cell recruitment. Despite the positive effect on recruitment and immune-tumor cell interaction, a lack of tumor cell killing is observed. The co-culture of PDAC organoids with stromal and immune cells grown on-a-Chip as described in this study indicates the suitability of microfluidic platforms for generating complex models and its use for dissecting complex cellular interplay and processes involved in the lack of anti-tumor immune responses in PDAC. Citation Format: Marlene Geyer, Sabrina D'Agosto, Henriëtte Lanz, Vincenzo Corbo, Jos Joore, Karla S. Queiroz. A novel microfluidic platform for understanding the role of PDAC stroma in immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3857.
Abstract 2393: Chemerin signaling presents a novel metabolic weakness in clear cell renal cell carcinoma (ccRCC)
Authors: Dazhi Wang
Journal: Cancer Research (2022)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer,accounting for 70-80% of the cases. While surgical resection of early-stage tumors remains the standard carefor patients, advanced ccRCC, metastatic or recurrent, portends a 5-year survival rate of only 12%, primarilydue to insensitivity toward conventional chemotherapy. ccRCC is identifiable histologically by its dramaticlipid storage phenotype, similar to adipocytes; yet the role of lipid metabolism in ccRCC is poorly understood.One of the well-established risk factors for ccRCC is obesity, and given that adipose tissue is known to producea variety of pro-adipogenic signaling molecules (called adipokines), we hypothesized that adipokine signalingmight be involved in the etiology of ccRCC. Our lab has recently identified a pro-tumorigenic adipokineprotein, chemerin (RARRES2), that is positively correlated with tumor aggressiveness. Suppression of chemerinvia either monoclonal antibody or siRNA led to reduction in lipid storage and significant tumor growthimpairment in both in vitro and in vivo models, suggesting the feasibility of targeting lipid metabolism as atreatment option in ccRCC patients. In this study, we investigate the signaling mechanisms of chemerin andhave found that chemerin drives downstream cellular activities and lipid deposition. We utilized CRISPR toknockout two candidate receptors of chemerin, GPR1 and CMLKR1, to gain insight into the signal transduction.CMLKR1 is a G-protein coupled receptor widely expressed on a variety of immune cells whereas GPR1expression is reported primarily in adipose tissues. While unknown on their detailed signaling cascadez, bothreceptors affect lipid metabolism related gene profiles in our ccRCC cell lines. Furthermore, both GPR1 andCMKLR1 knockout lead to growth suppression and decreased intracellular lipid deposition, highlighting theinvolvement of both receptors in regulating lipid metabolism and conferring growth advantage in ccRCC. Ourdata so far have shown the feasibility of identifying metabolic weaknesses in ccRCC, raising that possibility thattargeting lipid metabolism could be beneficial in ccRCC. Further investigation will be conducted to assess thetargetability of this ligand/receptor axis and various in vivo models including PDX and transgenic will be usedto assess the translational potential of our findings. Citation Format: Dazhi Wang. Chemerin signaling presents a novel metabolic weakness in clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2393.
Abstract 844: Germline <i>TP53</i> missense mutations at codon338 confer adult-onset cancer risk through weakened p53 protein oligomeric stability that impairs its tumor suppressive mechanisms
Authors: Nicholas W. Fischer, Jaime Turk, Noel Ong, Shili Duan, Lilia Kaustov, Christian Kratz, Kristian Pajtler, Raymond Kim, Cheryl Arrowsmith, David Malkin
Journal: Cancer Research (2022)

Abstract Pathogenic TP53 germline variants predispose carriers to a high lifelong cancer risk in Li-Fraumeni syndrome (LFS). LFS presents as a broad phenotypic spectrum with highly variable age-of-onset and tumor types. The mechanisms leading to these phenotypic differences remain largely unknown, and many less frequent variants are not clinically defined as pathogenic or benign. Two missense mutations in the tetramerization domain of the p53 protein, F338S and F338C, have recently been of clinical interest; however, they are currently classified as variants of uncertain significance. Normally, p53 assembles as a tetrameric complex to bind DNA and transcriptionally regulate the expression of target genes involved in the cellular response to stress, acting as a crucial barrier to malignant transformation. Alterations to p53 structure can therefore lead to malfunction and ultimately tumor formation. Our structural analysis of the tetramerization domain demonstrates that F338S and F338C have significantly lower thermal stability compared to the wildtype protein. Furthermore, our functional assessments of apoptosis and the suppression of colony formation indicate that both variants operate with reduced tumor suppressor activity, although they maintain near wildtype functionality. We anticipate that our results will help to better understand why these mutations cause a history of predominantly adult-onset cancers in the affected families and could justify refining surveillance measures for these individuals. Citation Format: Nicholas W. Fischer, Jaime Turk, Noel Ong, Shili Duan, Lilia Kaustov, Christian Kratz, Kristian Pajtler, Raymond Kim, Cheryl Arrowsmith, David Malkin. Germline TP53 missense mutations at codon338 confer adult-onset cancer risk through weakened p53 protein oligomeric stability that impairs its tumor suppressive mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 844.
Abstract 1529: Role of bitter taste receptor in colon cancer
Authors: Krishan Jain, Sangita Bhattacharyya, Afreen Sayed, David Standing, Kathy Benich, Shahid Umar, Shrikant Anant, Scott Weir, Roy Jansen, Prasad Ravindra Dandawate
Journal: Cancer Research (2022)

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the US with 53,200 deaths projected in 2020. Although the disease affects older people, recent statistics show an increase in the younger population. CRC is a major problem in veterans and every year ~4,000 veterans are diagnosed with CRC within VA facilities. Hence, there is a dire need to identify novel signaling pathways as targets for therapy. Based on a bedside discovery in CRC patients, we observed that CRC patients complained about dysgeusia or taste alterations. There are 25 bitter taste receptors (TAS2R1-50, TAS2R60). Taste receptors utilize G-protein coupled receptors (GPCRs) and signal through calcium release. In preliminary studies, mining the Cancer Genome Atlas (TCGA) database, we have determined that TAS2R38 is upregulated in multiple cancers, including CRC. Moreover, the higher expression of TAS2R38 transcript in CRC compared to other cancers. Furthermore, we confirmed overexpression of TAS2R38 in CRC tissues and cell lines by immunohistochemistry and RT-PCR. Moreover, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), a TAS2R38 agonist, treatment activated calcium mobilization in HCT116 and DLD1 cells suggesting the functionality of the receptor. OdDHL also enhanced mRNA of interleukin (IL)-6 and IL-8 levels in the CRC cells. To determine whether expression of the receptor is affected in vivo, we conducted the dextran sodium sulfate (DSS)-induced acute colitis and colitis-associated cancer model (azoxymethane (AOM)-DSS) in C57BL/6 mice. TAS2R138, the mouse homolog of human TAS2R38 is overexpressed in crypt epithelial cells in the colitis and tumor tissues. These observations suggest that TAS2R38 is overexpressed in the CRC and may play a critical role in disease progression. Citation Format: Krishan Jain, Sangita Bhattacharyya, Afreen Sayed, David Standing, Kathy Benich, Shahid Umar, Shrikant Anant, Scott Weir, Roy Jansen, Prasad Ravindra Dandawate. Role of bitter taste receptor in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1529.